This proposal is designd to study the molecular, cellular, and animal pharmacology of 5-azadeoxycytidine (AZA-CdR) in order to evaluate, preclinically, the antileukemic potential of this nucleoside analog. Biochemical studies will be performed in order to elucidate the mechanism of action of AZA-CdR. The phosphorylation and deamination of AZA-CdR will be investigated using purified enzymes. The 5'triphosphate form of AZA-CdR will be synthesized enzymatically and its effects on DNA polymerase studied. The cytotoxic effects of AZA-CdR on cells in vitro will be investigated using the colony-forming assay. The effect of AZA-CdR on cell growth will be determined. Using synchronized cells the cell cycle specificity of the lethal action of AZA-CdR and its effect on cell cycle progression will be investigated. The effect of AZA-CdR on the intracellular pool sizes of deoxynucleotides and DNA synthesis will be determined. Pharmacokinetic studies will be performed to determine the half life and volume of distribution of AZA-CdR. All these data will be integrated to design interesting dose-schedules for AZA-CdR in mice with L1210 leukemia that are based on scientific rationale. Chemotherapy with AZA-CdR in the mice will be administered by continuous I.V. infusion 3 days after an I.V. injection of the L1210 leukemic cells. The toxicology of the dose-schedule of AZA-CdR which shows the most effective antileukemic activity will be investigated.